Patients with type 2 diabetes may not have impaired secretion of glucagon-like peptide-1 (GLP-1), researchers found.

Action Points

This is a systematic review of studies of GLP-1 secretion in patients with type 2 diabetes and meta-analyses of GLP-1 concentrations during an OGTT or meal test.

The study suggests that, in general, patients with type 2 diabetes do not exhibit reduced GLP-1 secretion in response to an OGGT or a meal test.

Patients with type 2 diabetes may not have impaired secretion of glucagon-like peptide-1 (GLP-1), researchers found.

Though many drugs target this well-known pathway, a meta-analysis of several trials revealed that patients with type 2 diabetes had similar levels of GLP-1 secretion as controls after an oral glucose tolerance test (OGTT) or a mixed meal, Filip Knop, MD, PhD, of Gentofte Hospital at the University of Copenhagen, and colleagues reported online in Diabetologia.

Problems with GLP-1 may arise elsewhere in the pathway, such as in "beta-cell resistance" to the hormone, they wrote.

"Our paper shows that the bulk of patients with type 2 diabetes exhibit normal GLP-1 responses," Knop told MedPage Today. "This implies that treatment of type 2 diabetes with GLP-1 receptor agonists should be looked upon as a supplementation to normal GLP-1 levels rather than as a substitution to patients with low GLP-1 levels."

Knop said the findings have implications for future development of GLP-1 therapies.

It's long been known that patients with diabetes have a reduced incretin effect -- and impaired secretion of GLP-1 was believed to be one of the main culprits.

But in recent years, researchers have debated whether patients with type 2 diabetes actually have reduced GLP-1 secretion compared with healthy controls.

Knop and colleagues conducted a meta-analysis of all current data on plasma GLP-1 responses after an OGTT or a meal test, totaling 22 trials with 554 patients -- 275 of whom had type 2 diabetes and 279 of whom served as controls.

They found that both groups of patients had similar secretion of total GLP-1 as evaluated from peak plasma concentrations (weighted mean difference 1.09 pmol/L, not significant).

Also, a subgroup analysis showed that type 2 diabetics had increased GLP-1 responses after a liquid mixed meal test and after a 50-g OGTT.

But type 2 diabetics did have reduced GLP-1 responses compared with controls after a solid mixed meal test. The researchers said the difference between solid and liquid meals could have something to do with variations in the absorption of nutrients among type 2 diabetes patients.

The findings "may suggest that the GLP-1 secretion profile could change shape during the progression of type 2 diabetes," the researchers wrote -- although they warned that the results need to be interpreted carefully due to the heterogeneity of the included trials.

Still, it's clear that type 2 diabetes patients do consistently have a reduced incretin effect, and the findings "support the idea that a deterioration in GLP-1 effect, rather than GLP-1 secretion, contributes to this deficiency."

For instance, hyperglycemia could lead to down-regulation of GLP-1 receptor expression on beta cells, creating a type of 'GLP-1 resistance' in these cells, they wrote.

"It has become 'common knowledge' that reduced secretion of GLP-1 is part of type 2 diabetic pathophysiology. But this misunderstanding is based on the first few published reports, which -- perhaps incidentally -- showed reduced postprandial responses of GLP-1," Knop said. "These initial findings constituted one of the incentives for the development of GLP-1-based drugs."

"We believe that the paper will change the conception of type 2 diabetic pathophysiology with regard to the secretion of the incretin hormone GLP-1," he added.

Notably, he and colleagues wrote, it "may have implications for the design of new drugs based on activation of the GLP-1 receptor or other modulations of the GLP-1 pathways."

The researchers reported no conflicts of interest.

Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

More in Endocrinology

MedPageToday is a trusted and reliable source for clinical and policy coverage that directly affects the lives and practices of health care professionals.

Physicians and other healthcare professionals may also receive Continuing Medical Education (CME) and Continuing Education (CE) credits at no cost for participating in MedPage Today-hosted educational activities.